Trial of J&J's canagliflozin boosts SGLT2 cardiovascular credentials

Invokana cuts risk of heart failure hospitalisation by a third

Johnson & Johnson's SGLT2 inhibitor Invokana has become the second drug in the SGLT2 inhibitor class to reduce cardiovascular outcomes in type 2 diabetes patients, but with an increased risk of lower-limb amputation.

The results of the CANVAS trial - presented at the American Diabetes Association meeting in San Diego - showed that Invokana (canagliflozin) reduced cardiovascular death, myocardial infarction and stroke by 14% compared to placebo in at-risk patients, and cut the risk of hospitalisation for heart failure by a third.

The finding backs up the landmark EMPA-REG trial of Eli Lilly and Boehringer Ingelheim's Jardiance (empagliflozin), which was reported in 2015 and provides the first hard evidence of an SGLT2 inhibitor class effect in improving cardiovascular outcomes. Since then Jardiance has had its cardiovascular outcomes data added to the label in the US, and J&J has said it will seek to do likewise for Invokana.

Putting the trials side by side reveals a similar level of effect but with a different spectrum of activity, with Jardiance doing better at reducing cardiovascular death while Invokana's effects were most evident on MI and stroke. The absolute numbers of events in both studies were fairly low however so it is a matter of debate whether there are true differences between the drugs' clinical profiles.

CANVAS also revealed that the chance of patients going on to need a lower-limb amputation - a complication of diabetes - was doubled with Invokana. That is in line with the labelling for the drug in the US - where Invokana has a black-box warning about amputation - and suggests that "care is warranted in the use of canagliflozin in patients at risk for amputation", according to the trial investigators.

Amputation rates weren't specifically looked at in the EMPA-REG trial, but the European Medicines Agency (EMA) said in February that while this phenomenon has been seen only with J&J's drug, care should be taken when prescribing all drugs in the class as "data available to date are limited and the risk may also apply to [other SGLT2 inhibitors]".

Doctors should consider stopping treatment if patients develop significant foot complications such as infection or skin ulcers, according to the EMA.

Analysts at Evercore ISI suggest that the amputation data could hold back Invokana while a Credit Suisse report takes a similar line, predicting that the increased evidence for an SGLT2 inhibitor class effect could end up benefiting Jardiance more than J&J's drug. It has been suggested that adding the EMPA-REG data to Jardiance label could boost peak sales of the drug by $1.7bn.

On the plus side for Invokana a second study called CANVAS-R added to the positive data finding that J&J's drug reduced the rate of kidney function decline by 40%. Renal damage is a key complication of diabetes and this effect of the drug on kidney outcomes will be explored further in the CREDENCE trial, which is due to report in 2019. Lilly and Boehringer have also said that EMPA-REG suggests Jardiance also has kidney-protecting effects.

Combined data from both CANVAS and CANVAS-R have been published in the New England Journal of Medicine.